Process for making 16, 17-epoxy steroids using t-butyl hydroperoxide



3,014,905 PROCESS FOR MAKENG 16,17-EPOXY STERQKDS USHN G t-BUHYL HYDRQPERGXIDE Nien=hu C. Yang, Chicago, ill... Richard A. Finne an, Detroit, Mich, and Richard E. Ray, Morton Grove, 111., assignors to G. B. Searle dz (10., Chicago, iii, a corporation of Delaware N Drawing. Filed Jan. 15, 2959, Ser. No. 786,913 7 QHaims. (Cl. 260-239.55)

The present invention relates to a novel method for the selective epoxidation of A -2O-oxo steroids to the corresponding 160:,l7oc-613OXY-2O-0X0 derivatives.

Typically, the selective epoxidation in the 16,17-position is conducted on compounds of the structural formula CHQR (ll-I; (ii/=0 O wherein R is a member of the class consisting of hydrogen, hydroxyl, and radicals of the type OAcyl; R is hydrogen or methyl, X is a member of the class consisting of --CH CHOH, and &O; and Y is a member of the class consisting of -CHOH, -C=O, and -CHOAcyl-. In the foregoing formula at least one additional double bond should be present in one of the positions 4(5) or 5(6) and a double bond can also be present in the 1(2)-position. The acyl radicals are those derived from saturated aliphatic hydrocarbon carboxylic acids and include formyl, acetyl, propionyl, butyryl, pentanoyl, and hexanoyl. Of special importance is the selective epoxidation of the corresponding 6- and 12- methyl derivatives and the 6,12-dimethyl derivatives.

The selective epoxidation in the 16,17-position is conveniently carried out by contacting the corresponding 4(5),16 or 5(6),l6-pregnadiene or the corresponding A atent t pregnatriene analog with tertiary butyl hydroperoxide in 1 the presence of a catalytic amount of a weak base in an inert solvent. Among the Weak bases which can be employed are dilute potassium hydroxide, benzyltrirnethylammonium hydroxide and similar quaternary ammonium hydroxides. homologous aromatic hydrocarbons, tertiary butanol and pentanol.

This novel procedure is selective to the 16,17-position and does not cause epoxidation of polyunsaturated steroids having double bonds in the 1(2) and in the 4(5)- positions as do the conventional methods using hydrogen peroxide and alkali or the peroxy acids. Since none of the other epoxides are formed, time consuming and costly separation procedures are eliminated. Furthermore, the present invention affords a higher yield of the 16,17- epoxides than the older methods.

The invention will be further illustrated by the following examples which are to be construed as illustrative only and not limiting this invention either in spirit or in scope. It will be apparent to those skilled in the art of organic synthesis that many modifications both of materials and methods may be practiced without departing from the invention. In these examples quantities of materials are given in parts by weight and temperatures in degrees centigrade C.).

Suitable inert solvents include benzene and v ?a.tentecl Dec- 26, 1961 Example 1 A solution of 1 part of 1d-dehydroprogesterone, 0.6 part of tertiary butyl hydroperoxide, 0.05 part of a 35% methanolic solution of benzyltrimethylammonium hydroxide and 5.3 parts of benzene is allowed to stand at room temperature for 12 hours. At the end of this time the reaction mixture is Washed with water. The aqueous washings are saturated with sodium chloride and extracted with ether. The organic extracts are combined, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. Upon recrystallization from methanol there is obtained 16a,17a-epoxy-4- pregnene-3,20-dione melting at about 205-207" C., with of +1566". Absorption is observed in the infrared at 5.87, 6.03, 6.21 and 11.29 microns.

Substitution of an equimolar amount of 21-hydroxy- 4,16-pregnadiene-3,20-dione or 21-acetoxy-4,16-pregnadiene-3,20-dione for the l6-dehydroprogester0ne in the preceding paragraph of this example yields 16a,17aepoxy-21-hydroxy-4-pregnene-3,ZO-dione melting at about 191-493 C.

Substitution of an equirnolar amount of 6a-rnethyl-16- dehydroprogesterone for the 16-dehydroprogesterone in the first paragraph of this example yields 6arn6'thy1-16a, 17m-epoxy-4-pregnene-3,20-dione melting at about 14.5 147 C.

Example 2 A solution of 0.5 part of 1,4,16-pregnatriene-3,20-dione, 0.91 part of a 62% methanolic solution of tertiary butyl hydroperoxide, 0.09 part of potassium hydroxide, 4.7 parts of tertiary butyl alcohol and 0.5 part of water is dissolved in 21 parts of tertiary butanol. The mixture is allowed to stand at room temperature for 4 hours and then cold water is slowly added until crystals appear. The resulting crystalline mixture is cooled to 0 C. and permitted to stand for 1 hour. The crystals are then filtered, dried and recrystallized from a mixture of methanol and water. In this manner there is obtained 16u,17a-epoxy-1,4-pregnadiene-3,20-dione melting at about ISO-183 C. The compound shows absorption in the ultraviolet at 244 millimicrons with an extinction coefficient of 16,900. Infrared maxima are observed at 5.85, 6.01 and 6.17 microns.

Substitution of an equimolar amount of 21-hydroxy- 1,4,16-pregnatriene-3,20-dione or 21-acetoxy-1,4,16-pregnatriene-3,20-dione for the 1,4,16-pregnatriene-3,20-dione in the preceding paragraph of this example yields 16oc,17ocepoxy-21-hydroxy-1,4-pregnadiene-3,20-dione. The compound shows absorption in the ultraviolet at 244 millimicrons with a molecular extinction coefiicient of 16,500.

Example 3 To a solution of: 2 parts of 3B-hydroxy-5(6),16-pregnadien-ZO-one in 86 parts of tertiary butanol is added a solution of 0.39 part of potassium hydroxide dissolved in 19.2 parts of tertiary butanol, 2 parts of water, and 3.62 parts or" a 62% methanolic solution of tertiary butyl hydroperoxide. The mixture is allowed to stand at room temperature for 7 hours. At the end of this time sufficient water is added to the reaction mixture to reduce the alcohol content to 15%. The solution is extracted with ether. The ethereal extracts are dried over magnesium sulfate and taken to dryness under vacuum. Upon recrystallization from a mixture of methanol and Water there is obtained 3B hydroxy-16a,17a-epoxy-5 (6) -pregnen-20-one melting at about l92l93 C. Infrared maxima are observed at 2.77 and 5.83 microns.

Substitution of an equimolar amount of 3,6,2l-dihydroxy-S(6),16-pregnadien-20 one or 35,21 diacetoxy- 5(6),l6-pregnadien-20-one for the 3/3-hydroxy-5(6),16- pregnadien-ZO-one in the preceding paragraph of this example yields pregnenQO-one.

Example 4 To a solution of 2 parts of 3,8-acetoxy-6-methyl-5(6),- 16-pregnadieu-20-one in 88 parts of tertiary butyl alcohol is added a solution of 0.86 part of potassium hydroxide dissolved in 44 parts of tertiary butanol, 4 parts of Water, and 20 parts of a 62% methanolic solution of tertiary butyl hydroperoxide. The mixture is stirred at room temperature for 5 hours. At the end of this time sufficient water is added to the reaction mixture to reduce the alcohol content to The product is collected by filtration. Upon recrystallization from a mixture of methanol and water, there is obtained EMS-hydroxy-6-methyl-16a,17u-epoxy-5(6) pregnene -one melting at about 182-185 C.

Example 5 To a solution of 0.5 part of 4,l6-pregnadiene-3,l1,20-

trione in 6.1 parts of dry benzene is added a solution of 0.35 part or" a 62% methanolic solution of tertiary butyl hydroperoxide and 4 drops of a methanolic solu tion of benzyltrimethylammonium hydroxide. The reaction mixture is then stirred at room temperature for 5 hours, at the end of which time 8.8 parts of benzene are added. The solution is washed with water and then with saturated sodium chloride solution. The solvent is vacuum distilled and the residue is recrystallized from a solution of acetone and petroleum ether. In this manner there is obtained 16a,17m-epoxy-4-pregnene-3J1,20- trione melting at about 187-189 C. The compound shows absorption in the ultraviolet at 238 millimicrons with an extinction coefiicient of 15,200. Infrared maxima are observed at 5.82, 5.99 and 6.19 microns.

Substitution of an equimolar amount of 21-hydroxy- 4,16-pregnadiene-3,l1,20-trione or 21-acetoxy-4,16-pregnadiene-3,l1,20-trione for the 4,l6-pregnadiene-3,l1,20- trione in the -receding paragraph of this example yields 16a,17u-epoxy-2l-hydroxy-4-pregnene-3 ,11,20-trione.

What is claimed is:

l. The process for the selective epoxidation of a A -3,20-dioxo steroid to the corresponding A 460:- 17u-epoxy-20-oxo steroid which comprises contacting the steroid with at least one molecular equivalent of tertiary butyl hydroperoxide in the presence of a catalytic amount of a base which is a member of the class consisting of dilute solutions of inorganic hydroxides and quaternary ammonium hydroxides in an inert solvent.

2. The process for the preparation of 16a,l7a-epoxy- 4-pregnene-3,20-dione which comprises contacting 16- dehydroprogesterone with at least one molecular equivalent of tertiary butyl hydroperoxide in the presence of a catalytic amount of a base which is a member of the class consisting of dilute solutions of inorganic hydroxides and quaternary ammonium hydroxides in an inert solvent.

3. The process for the preparation of 16a,17a-epoxy- 1,4-pregnadiene-3,20-dione which comprises contacting 1,4,16-pregnatriene-3,20-dione with at least one molecular equivalent of tertiary butyl hydroperoxide in the presence of a catalytic amount of a base which is a member of the class consisting of dilute solutions of inorganic hydroxides and quaternary ammonium hydroxides in an inert solvent.

4. The process for the preparation of 16a,l7a-epoxy- 4-pregnene-3,l1,20-trione which comprises contacting 4,16-pregnadiene-3,11,20-trione with at least one molecular equivalent of tertiary butyl hydroperoxide in the presence of a catalytic amount of a base which is a member of the class consisting of dilute solutions of inorganic hydroxides and quaternary ammonium hydroxides in an inert solvent.

5. The process for the preparation of 160:,l7oc-6POXY- 2l-hydroxy-4-pregnene-3,ZO-dionc which comprises contacting a member of the class consisting of 21-hydroxy- 4,16-pregnadiene-3,20-dione and 21-acetoxy-4,16-pregnadieneSJO-dione with tertiary butyl hydroperoxide in the presence of a catalytic amount of a base which is a member of the class consisting of dilute solutions of inorganic hydroxides and quaternary ammonium hydroxides in an inert solvent.

6. The process for the preparation of l6a,'l7a-epoxy- 2l-hydroxy-l,4-pregnadiene-3,ZO-dione which comprises contacting a member of the class consisting of 21-hydroxy 1,4,l6-pregnatriene-3,20-dione and ZI-acetoxy- 1,4,16-pregnatriene-3,20-dione with at least one molecular equivalent of tertiary butyl hydroperoxide in the presence of a catalytic amount of a base which is a member of the class consisting of dilute solutions of inorganic hydroxides and quaternary ammonium hydroxides in an inert solvent.

7. The process for the preparation of 16a,l7a-epoxy- 2l-hydroxy-4-pregnene-3,l1,20-trione which comprises contacting a member of the class consisting of Zl-hydrovy-4,16-pregnadiene-3,l1,20-trione and 2l-acetoxy- 4,16-pregnadiene-3,l1,20-trione with at least one molecular equivalent of tertiary butyl hydroperoxide in the presence of a catalytic amount of a base which is a member of the class consisting of dilute solutions of inorganic hydroxides and quaternary ammonium hydroxides in an inert solvent.

References Cited in the tile of this patent UNITED STATES PATENTS 2,684,364 Jones July 20, 1954 2,705,233 Julian Mar. 29, 1955 2,752,340 Ehrhart et al. June 26, 1956 2,776,301 Payne et al. Jan. 1, 1957 OTHER REPE ENCES Yang et al.: J. Am. Chem. Soc, vol. (Nov. 5, 1958), pages 5845-5843 (pages 5846 and 5848 necessary). 

1. THE PROCESS FOR THE SELECTIVE EPOXIDATION OF A $4,16-3,20-DIOXO STEROID WHICH COMPRISES COHTACTING 17A-EPOXY-20-OXO STERIOD WHICH COMPRISES CONTACTING THE STERIOD WITH AT LEAST ONE MOLECULAR EQUIVALENT OF TERTIARY BUTYL HYDROPEROXIDE IN THE PRESENCE OF A CATALYTIC AMOUNT OF A BASE WHICH IS A MEMBER OF THE CLASS CONSISTING OF DILUTE SOLUTIONS OF INORGANIC HYDROXIDES AND QUATERNARY AMMONIUM HYDROXIDES IN AN INERT SOLVENT. 